center for drug evaluation and research · 2013. 4. 30. · pharmacologic class: nonsteroidal...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER: 204768Orig1s000

PHARMACOLOGY REVIEW(S)

1

DEPARTMENT OF HEALTH AND HUMAN SERVICESPUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATIONCENTER FOR DRUG EVALUATION AND RESEARCH

PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION

Application number: 204-768

Supporting document/s: 000/Original submission

CDER stamp date: 4/30/2013

Product: Tivorbex® (Indomethacin)

Indication: Treatment of mild to moderate acute pain

Applicant: Iroko Pharmaceuticals, LLC, Philadelphia, PA

Review Division: Division of Anesthesia, Analgesia, and Addiction Products (HFD-170)

Reviewer: Z. Alex Xu, PhD, DABT

Supervisor/Team Leader: Adam Wasserman, PhD

Division Director: Bob Rappaport, MD

Project Manager: Kimberly Compton

Disclaimer

Except as specifically identified, all data and information discussed below and necessary for approval of NDA 204-768 are owned by Iroko Pharmaceuticals, LLC or are data for which Iroko Pharmaceuticals, LLC has obtained a written right of reference.Any information or data necessary for approval of NDA 204-768 that Iroko Pharmaceuticals, LLC does not own or have a written right to reference constitutes one of the following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or information described or referenced below from reviews or publicly available summaries of a previously approved application is for descriptive purposes only and is not relied upon for approval of NDA 204-768.

Reference ID: 3438978

NDA 204-768 Reviewer: Z. Alex Xu

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TABLE OF CONTENTS

1 EXECUTIVE SUMMARY ......................................................................................... 3

1.1 INTRODUCTION .................................................................................................... 31.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 41.3 RECOMMENDATIONS ............................................................................................ 6

2 DRUG INFORMATION ............................................................................................ 8

2.1 DRUG ................................................................................................................. 82.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 82.3 DRUG FORMULATION ........................................................................................... 92.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 102.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 102.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 122.7 REGULATORY BACKGROUND .............................................................................. 12

3 STUDIES SUBMITTED.......................................................................................... 12

3.1 STUDIES REVIEWED........................................................................................... 123.2 STUDIES NOT REVIEWED ................................................................................... 133.3 PREVIOUS REVIEWS REFERENCED...................................................................... 13

4 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 13

5 SPECIAL TOXICOLOGY STUDIES ...................................................................... 14

6 LITERATURE SUBMISSION................................................................................. 17

7 APPENDIX/ATTACHMENTS................................................................................. 18



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to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.

Labor or DeliveryThe effects of TIVORBEX on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival.

Data

Animal data

Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.16 times [mice] and 0.32 times [rats] the maximum recommended human dose [MRHD] on a mg/m

2basis, respectively)

considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.20 to 0.60 times MRHD on a mg/m

2basis) have

described maternal toxicity and death, increased fetal resorptions, and fetal malformations. Comparable studies in rodents using high doses of aspirin have shown similar maternal and fetal effects.

Maternal indomethacin administration of 4.0 mg/kg/day during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups. Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level.

8.3 Nursing Mothers

Based on available published data, indomethacin may be present in human milk. In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average dose present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in the breast milk of 8 postpartum women using doses of 75 mg daily and the results were used to calculate an infant daily dose. The estimated infant dose of indomethacin breast milk was less than 30 µg/day or 4.5 µg/ kg/day assuming breast milk intake of 150 ml/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for TIVORBEX and any potential adverse effects on the human milk-fed child from the drug or from the underlying maternal condition. Exercise caution when TIVORBEX is administered to a nursing woman.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis: In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.08 times the MRHD on a mg/m

2basis), indomethacin had no tumorigenic effect. Indomethacin

produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses


(b) (4)

(b) (4)


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up to 1.5 mg/kg/day (0.06 times [mice] and 0.12 times [rats] the MRHD on a mg/m2

basis, respectively).

Mutagenesis: Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the

host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.

Impairment of Fertility: Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect onfertility in mice in a two generation reproduction study (0.02 times the MRHD on a mg/m

2basis)

or a two litter reproduction study in rats (0.04 times the MRHD on a mg/m2

basis).

2 Drug Information

2.1 Drug

CAS Registry Number (Optional)

Generic Name Indomethacin

Code Name Indomethacin

Chemical Name: 1-(ρ-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid

Molecular Formula/Molecular Weight

C19H16ClNO4; MW = 357.8Structure or Biochemical Description

Pharmacologic Class: Nonsteroidal Anti-inflammatory Drug

2.2 Relevant INDs, NDAs, BLAs and DMFs

Tivorbex was developed under IND 101,940. The drug substance referenced DMF Approved indomethacin drug products are shown in the table below.


(b) (4)

(b) (4)


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The assessment was performed with a computer-based expert system consisting of the MC4PC software and 4 sets of carefully designed expert modules, i.e., two sets for rodent carcinogenicity (public domain and proprietary), one set for cardiotoxicity, and one regulatory relevant set for genotoxic potential. The modules were developed by the CTG group of the US FDA with MultiCASE Inc. MC4PC is a knowledge-based system designed to evaluate the associations between the structure of the chemicals and their potential activities in a specific biological assay. Its main goal is to find the structural entities that discriminate active molecules from inactive ones and its success is dependent on the validity of the working hypothesis that a relationship exists between chemical structure and activity. The results of the assessment were summarized in the following table as extracted from the study report. The RCA (Research Cooperative Agreement with FDA) method expert analysis is a protocol currently used to perform human expert prediction of toxicity for test chemicals by processing MC4PC output data and identify structural alerts across multiple toxicologically related endpoints. The process typically involves combining data obtained from a module set consisting of modules representing 3-6 (as many as 20) closely related endpoints. Based on the RCA analysis, all 5 compounds were predicted to be negative in the Ames assay, in vitro gene mutation assay (MA in vitro), in vitro chromosomal assay (CA in vitro), in vivo micronucleus assay (MN in vivo), and in vivo gene mutation assay (MA in vivo). However, were predicted to be positive in the in vitro chromosomal assay (CA in vitro); these compounds were identified to containgenotoxic structural alert groups. The conclusion from review experts was inconclusive for the CA in vitro model taking into account all the available evidence. Therefore, it was concluded in this study report that overall, the 5 compounds did not demonstrate convincing evidence of activity in genotoxicity test assessments. Of note, possible structure coverage problems were identified in some of the assessments as indicated below.


(b) (4)

(b) (4)


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7 Appendix/Attachments

List of publications submitted by the Applicant

1. Abatan MO, Lateef I, Taiwo VO. Toxic effects of non-steroidal anti-inflammatoryagents. African J Biomed Research. 2006; 9: 219-223.

2. Bakalova R, Matsuura T, Kanno I. The cyclooxygenase inhibitors indomethacin androfecoxib reduce regional cerebral blood flow evoked by somatosensory stimulation inrats. Exper Bio and Med 2002; 227:465-473.

3. Black HE. Renal toxicity of non-steroidal anti-inflammatory drugs. Toxico Pathol 1986; 14(1): 83-90.

4. Brix AE. Renal papillary necrosis. Toxicol Pathol 2002; 30:672-674. Available from:http://tpx.sagepub.com/content/30/6/672: DOI: 10.1080/01926230290166760

5. "CCRIS" Chemical Carcinogenesis Research Information System [Internet]. Bethesda (MD): United States national Library of Medicine/s TOXNET System; [cited 2012 September 27]. Indomethacin, CAS Registry Number 53-86-1 [41 p]. Last Revision Date 20100602. Available from: http://toxnet.nlm.nih.gov:file:///C:/Users/PHARMA~1/AppData/Local/Temp/Low/W4ETV3H8.htm

6. ChemIDPlus Advanced [Internet]. Bethesda (MD): United States National Library ofMedicine’s Chem SIS System; [cited 2013 January 26]. Indomethacin. CAS RegistryNumber 53-86-1[about 7 p]. Available from:http://chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?objectHandle=Search&actionHandle=getAll3DMViewFiles&nextPage=jsp%2Fcommon%2FChemFull.jsp%3FcalledFrom%3Dlite&chemid=0000053861&formatType=_3D

7. ChemIDPlus Advanced [Internet]. Bethesda (MD): United States National Library ofMedicine’s Chem SIS System; [cited 2013 February 07]. 5-Methoxy-methylindoleaceticacid. CAS Registry Number 2882-15-7 [about 2 p]. Available from:http://chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?objectHandle=DBMaint&actionHandle=default&nextPage=jsp/chemidheavy/ResultScreen.jsp&ROW_NUM=0&TXTSUPERLISTID=0002882157

8. ChemIDPlus Advanced [Internet]. Bethesda (MD): United States National Library ofMedicine’s Chem SIS System; [cited 2013 February 07]. p-Chlorobenzoic acid. CASRegistry Number 74-11-3 [about 3 p]. Available from:http://chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?objectHandle=DBMaint&actionHandle=default&nextPage=jsp/chemidheavy/ResultScreen.jsp&ROW_NUM=0&TXTSUPERLISTID=0000074113

9. Cook JC, Jacobson CF, Gao F, Tassinari MS, Hurtt ME, DeSesso JM. Analysis of thenonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats



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and rabbits. Birth Defects Research (Part B) 2003; 68:5-26.

10. DrugBank: a knowledgebase for drugs, drug actions and drug targets. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M. Nucleic Acids Res. 2008 Jan; 36(Database issue):D901-6. PMID: 18048412. Available from:http://www.drugbank.ca/drugs/DB00328

11. Duggan DE, Hogans AF, Kwan KC, McMahon, FG. The metabolism of indomethacin in man. J Pharmacol Exp Ther 1972; 181:563-575.

12. Duggan DE, Hooke KF, Noll RM, Kwan, KC. Enterohepatic circulation of indomethacin and its role in intestinal irritation. Biochem Pharm 1975; 25:1749-1754

13. Fan JL, Burgess KR, Thomas KN, Peebles KC, Lucas SJ, Lucas RA, Cotter JD, Ainslie PN. Influence of indomethacin on ventilatory and cerebrovascular responsiveness to CO2 and breathing stability: the influence of PCO2 gradients. Am J Physiol Regul Integr Comp Physiol 2010; 298:R1648-R1658.

14. FDA Orange Book [Internet]. Bethesda (MD); [cited 2013 February 28]. Approved drug products with therapeutic equivalence evaluations. Current through January 2013.Available from: http://www.accessdata.fda.gov/scripts/cder/ob/docs/tempai.cfm

15. Genelex P450 Drug Interactions Tables [internet]. Seattle (WA); [cited 2012 September 16]. P450 Drug-Interactions Substrates, Inhibitors and Inducers [about 2 p]. Available from: http://www.genemedrx.com/Cytochrome P450 Metabolism Table.php

16. Gretzer B, Maricic N, Respondek M, Schuligoi R, Peskar BM. Effects of specificinhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the rat stomach with normalmucosa and after acid challenge. British J Pharmacol. 2001; 132: 1565-1573.

17. Grosser T, Smyth E, FitzGerald, GA. Anti-inflammatory, antipyretic and analgesicagents; Pharmacotherapy of Gout. In Goodman and Gilman’s Pharmacological Basis ofTherapeutics, 12th Edition 2011; Chapter 34; 959-1004.

18. Guidechem Material Safety Data Sheet [Internet] [cited 7 February 2013]. 1H-Indole-3- aceticacid, 5-methoxy-2-methyl- CAS Registry Number 2882-15-7 [about 5 p].Available from: http://img1.guidechem.com/msdspdf/2882-15-7.pdf

19. "HSDB" Hazardous Substances Data Bank [Internet]. Bethesda (MD): United StatesNational Library of Medicine; [cited 2013 January 5]. Indomethacin, CAS RegistryNumber 53-86-1 [79 p]. Last Revision Date 20120806. Available from:http://toxnet.nlm.nih.gov/cgi-bin/sis/

20. Hucker HB, Zacchei AG, Cox SV, Brodie DA, Cantwell, NHR. Studies on theabsorption, distribution and excretion of indomethacin in various species. J Pharm ExpTherapeu 1966; 153(2): 237-249



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21. ICH Harmonized Tripartite Guideline: Q3A(R2) Impurities in New Drug Substances.CDER, Pharmacology/Toxicology. October 2006

22. ICH Harmonized Tripartite Guideline: Q3B(R2) Impurities in New Drug Products.CDER, Pharmacology/Toxicology. June 2006.

23. ICH Harmonized M7 Step 1 Document: Assessment and Control of DNA Reactive(Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. EWGSevilla Meeting, 15 November, 2011.

24. Kristensen DM, Hass U, Lesné L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C,Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jégou B, Leffers H. Intrauterine exposure to mild analgesics is a risk factorfor development of male reproductive disorders in human and rat. Human Repro 2011;26(1):235-244.

25. Kristensen DM, Lesné L, LeFol V, Desdoits-Lethimonier C, Dujucq-Rainsford N,Leffers H, Jégou, B. Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) andindomethacin are anti-androgenic in the rat foetal testis. In J Andrology 2012; 35:377-384.

26. "LACT" Drug and Lactation Database [Internet]. Bethesda (MD): United States National Library of Medicine’s ToxNet System; [cited 2012 April 05]. Indomethacin, CASRegistry Number 53-86-1 [about 3 p]. Available from: http://toxnet.nlm.nih.gov/cgibin/sis/search/f?./temp/~roBwME:1

27. Lebedevs TH, Wojnar-Horton RE, Yapp P, Roberts MJ, Dusci LJ, Hackett LP, Ilett KF. Excretion of indomethacin in breast milk. Br J Clin Pharmac, 1991; 32:751-754.

28. Lim E, Pon A, Djoumbou Y, Knox C, Shrivastava S, Guo AC, Neveu V, Wishart DS.T3DB: a comprehensively annotated database of common toxins and their targets.Nucleic Acids Res. 2010 Jan 38(Database issue):D781-6.

29. Mano Y, Usui T, Kamimura H. Contribution of UDP-glucuronosyltansferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver. Eur J Clin Pharmacol 2007;63:289-296.

30. Markus HS, Vallance P, Brown MM. Differential effect of three cyclooxygenaseinhibitors on human cerebral blood flow velocity and carbon dioxide reactivity. Stroke.1994; 25(9):1760-1764.

31. Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse DrugReactions and Interactions (Fifteenth Edition),Indomethacin. Editor: Aronson JK,Editor(s)-in-Chief, Elsevier, Amsterdam, 2006:1739-1746. Available from:http://www.sciencedirect.com/science/article/pii/B0444510052012663



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32. Mylan Indomethacin Capsules USP 50 mg [Prescribing Information]. Morgantown, WV: Mylan Institutional Inc; 2012. [about 12 p]. Available from:http://druginserts.com/lib/rx/meds/indomethacin-35/page/3

33. Nakajima M, Inoue T, Shimada N, Tokudome S, Yamamoto T, Kuroiwa Y. Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. Drug Metab and Dispos 1998;26(3):261-266. P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes. DrugMetab and Dispos 1998;26(3):261-266.

34. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ 2001; 322:266-270.

35. Noergaard MH, Pedersen DB, Bang K, Jensen PK, Kiilgaard JF, Stefansson E, la Cour M. Indomethacin decreases optic nerve oxygen tension by a mechanism other than cyclooxygenase inhibition. Br J Ophthalmol 2008; 92:126–130. Available from:http://bjo.bmj.com/ (doi:10.1136/bjo.2007.122309).

36. O'Brien M, McCauley J, Cohen E. Indomethacin. In Analytical Profiles of DrugSubstances, 1984; 13:211-238.

37. Schneider HT, Nuernberg B, Dietzel K, Brune K. Biliary elimination of non-steroidalanti-inflammatory drugs in patients. Br J Clin Pharmac 1990; 29:127-131.

38. Sigma-Aldrich Material Safety Data Sheet . 4-Chlorobenzoic acid. CAS Registry Number 74-11-3. Version 3.3, last updated 29 October 2012 [about 7 p].

39. Sood BG, Lulic-Botica M, Holzhausen KA, Pruder S, Kellogg H, Salari V, Thomas R.The risk of necrotizing enterocolitis after indomethacin tocolysis. Pediatrics2011;128:e54-e62 Available from: http://pediatrics.aappublications.org/content/128/1/e54.full.html

40. Stacy ZA, Dobesh PP, Trujillo TC. Cardiovascular risks of cyclooxygenase inhibition. Pharmacotherapy 2006; 26(7):919-938.

41. Thomson MicromedexTM. Drug Information for the Health Care Professional. USP DI. : Micromedex, Greenwood Village, CO; 24th Edition 2004. 374-397.

42. Tsubota K, Kushima K, Yamauchi K, Matsuo S, Saegusa T, Ito S, Fjuiwara M,Matsumoto M, Nakatsuji S, Seki J, Oishi Y. Collaborative work on evaluation of ovariantoxicity 12) Effects of 2- or 4-week repeated dose studies and fertility study ofindomethacin in female rats. J Toxicol Sci 2009; 34:Special Issue I: SP1129-SP136.



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43. Yesair DW, Callahan M, Remington L, Kensler CJ. Role of the entero-hepatic cycle of indomethacin on its metabolism, distribution in tissues and its excretion by rats, dogs and monkeys. Biochem Pharm 1970;19:1579-1590.

44. Zhou Y, Dial EJ, Doyen R, Lichtenberger LM. Effect of indomethacin on bile acidphospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs. Am J Physiol Gastrointest Liver Physiol 2010; 298:G722-G731.


---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

ZENGJUN XU01/18/2014

ADAM M WASSERMAN01/20/2014I concur with the recommendation for approval from the nonclinical perspective.


PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR NDA/BLA or Supplement

Pharmacology Toxicology Filing Checklist for NDA 204-768

NDA/BLA Number: 204-768 Applicant: Iroko Pharmaceutical, LLC

Stamp Date: 04/30/2013

Drug Name: Capsule (Indomethacin)

NDA/BLA Type: 505 (b)(2)

On initial overview of the NDA/BLA application for filing:

Content Parameter

Yes

No

Comment 1 Is the pharmacology/toxicology section

organized in accord with current regulations and guidelines for format and content in a manner to allow substantive review to begin?

√

2

Is the pharmacology/toxicology section indexed and paginated in a manner allowing substantive review to begin?

√

3

Is the pharmacology/toxicology section legible so that substantive review can begin?

√

4

Are all required (*) and requested IND studies (in accord with 505 b1 and b2 including referenced literature) completed and submitted (carcinogenicity, mutagenicity, teratogenicity, effects on fertility, juvenile studies, acute and repeat dose adult animal studies, animal ADME studies, safety pharmacology, etc)?

√

5

If the formulation to be marketed is different from the formulation used in the toxicology studies, have studies by the appropriate route been conducted with appropriate formulations? (For other than the oral route, some studies may be by routes different from the clinical route intentionally and by desire of the FDA).

NA

No animal toxicity studies are required for the approval of this drug product

6

Does the route of administration used in the animal studies appear to be the same as the intended human exposure route? If not, has the applicant submitted a rationale to justify the alternative route?

√

7 Has the applicant submitted a statement(s) that all of the pivotal pharm/tox studies have been performed in accordance with the GLP regulations (21 CFR 58) or an explanation for any significant deviations?

NA

No animal toxicity studies are required for the approval of this drug product

8 Has the applicant submitted all special studies/data requested by the Division during pre-submission discussions?

√


(b) (4)

PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR NDA/BLA or Supplement

Pharmacology Toxicology Filing Checklist for NDA 204-768

Content Parameter

Yes

No

Comment

9 Are the proposed labeling sections relative to pharmacology/toxicology appropriate (including human dose multiples expressed in either mg/m2 or comparative serum/plasma levels) and in accordance with 201.57?

√

Human dose multiples were not included in the description of nonclinical studies. However, it is not considered an issue which needs to inform the Applicant in the 74-day letter. The human dose multiples can be easily added during the labeling negotiation

10 Have any impurity – etc. issues been addressed? (New toxicity studies may not be needed.)

√

11 Has the applicant addressed any abuse potential issues in the submission? NA

12 If this NDA/BLA is to support a Rx to OTC switch, have all relevant studies been submitted?

X

This NDA is not to support a Rx to OTC switch

IS THE PHARMACOLOGY/TOXICOLOGY SECTION OF THE APPLICATION FILEABLE? _____yes___ If the NDA/BLA is not fileable from the pharmacology/toxicology perspective, state the reasons and provide comments to be sent to the Applicant. Please identify and list any potential review issues to be forwarded to the Applicant for the 74-day letter. None Z. Alex Xu 06/26/2013 Reviewing Pharmacologist Date Adam Wasserman 06/26/2013 Team Leader/Supervisor Date


---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

ZENGJUN XU06/26/2013

ADAM M WASSERMAN06/27/2013


center for drug evaluation and research · 2013. 4. 30. · pharmacologic class: nonsteroidal...

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